Various antiphlogistic and analgesic agents are known but it is generally found that the antiphlogistic and analgesic agents conventionally used have a rather high toxicity and often induce various undesired side effects such as for example gastric lesions. There is thus a need for antiphlogistic and analgesic agents having a lower toxicity and no undesired side effects.
It is known that chloro-5-benzo(b)furyl-2 carboxylic acid, chloro-5 benzoful-2-acetate, methoxy-5 benzo(b)furyl-2-acetate and a derivative of substituted .beta.-(benzofuyl-2)acrylic acid have a lower anti-inflammatory activity and a minor toxicity than phenylbutazone (Eur. J. Med. Chem.--Chimica Therapeutica, March-April 1975-10, N. 2, p. 182-186).
The present invention is concerned with the following 5-substituted-3-methyl-2-benzo(b)furylacetic acids of general formula ##STR1## wherein R represents a hydrogen atom; an alkyl group containing 1 to 6 carbon atoms, e.g. a methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl or n-hexyl group; an alkoxy group containing 1 to 6 carbon atoms, e.g. a methoxy, ethoxy, n-propoxy or isopropoxy group; a cycloalkyl group containing 3 to 6 carbon atoms, e.g. a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group; a cycloalkoxy group containing 3 to 6 carbon atoms, e.g. a cyclopropoxy group; an alkenyl group containing 3 or 4 carbon atoms, e.g. a propenyl or 1-butenyl group; an alkenyloxy group containing 3 or 4 carbon atoms, e.g. a propenyloxy or isopropenyloxy group; a cyclohexenyloxy group; a phenyl group or a substituted phenyl group having the formula ##STR2## wherein R.sub.1 represents a methoxy group; a halogen atom, e.g. a fluorine or chlorine atom; or an alkyl group containing 1 to 4 carbon atoms, e.g. a methyl, ethyl, propyl, n-butyl, sec-butyl or tert-butyl group; a phenoxy group; a benzyl group; a substituted benzyl group having the formula: ##STR3## wherein R.sub.1 is as defined above; a trifluoromethyl group; or a halogen atom, e.g. a fluorine, chlorine or bromine atom and phsyiologically acceptable salts thereof.
The present invention is further concerned with the discovery that the 5-substituted-3-methyl-2-benzo(b)furylacetic acids of general formula (I) show antiphlogistic and analgesic activities.
Thus according to the present invention there are provided pharmaceutical compositions comprising as active ingredient a compound of formula (I) as hereinbefore defined or a physiologically acceptable salt thereof in association with a pharmaceutical carrier or excipient.
Among the derivatives of benzo(b)furylacetic acid represented by the formula (I), the derivatives where R is a hydrogen atom [Chem. Ber. 97, 3577 (1964)], a methyl radical [Rocz. Chem. 44, 1913 (1970)] and a chlorine atom [Indian Journal of Chem., 2, 456 (1964)] were previously known, although it was not known that these compounds had antiphlogistic and analgesic properties. The other compounds of general formula (I) are however new compounds and constitute a further feature of the present invention.
The preparations of the three known compounds, 3-methyl-2-benzo(b)furylacetic acid, 3,5-dimethyl-2-benzo(b)furylacetic acid and 5-chloro-3-methyl-2-benzo(b)furylacetic acid are described in the above indicated literature references. However, these preparations have disadvantages of complicated steps and a low yield.
The present invention is accordingly to provide processes for preparing the derivatives of benzo(b)furylacetic acid of the formula (I) with a high yield in a simple manner. According to the present invention, the derivatives of benzo(b)furylacetic acid represented by the formula (I) can be prepared by the process exemplified as follows:
(A) Process using as a starting material 3-methyl-2-cyanomethylbenzo(b)furan or 5-substituted derivatives thereof having the general formula (II) ##STR4## wherein R is as hereinbefore defined.
The compounds of general formula (I) can be prepared from the starting compound by hydrolysis in an aqueous medium in the presence of an acid or alkali.
Acids which are preferably used for this purpose are, for example, hydrochloric acid, sulfuric acid, phosphoric acid and para-toluenesulfonic acid. It is also possible to use a strongly acidic ion exchange resin.
Alkalis which are preferably used for this purpose are, for example, hydroxides of alkali metals and alkaline earth metals, e.g. sodium hydroxide, potassium hydroxide and calcium hydroxide.
The hydrolysis is preferably effected in the presence of a solvent, especially an organic solvent which does not react with the starting compound and which is miscible with water. Preferred organic solvents include, for example, dioxane, tetrahydrofuran, acetone, 2-methoxyethanol, 2-ethoxyethanol and lower alcohols, e.g. methanol, ethanol, n-propanol, isopropanol, n-butanol and tert-butanol. Advantageously the organic solvent is present in an amount of from 1/4 to 4 times the volume of water. In the reaction, 0.01 mole to 1.0 mole, preferably 0.1 mole-0.5 mole, of the starting compound is used per one liter of the total solvent.
The reaction is usually carried out at a temperature within the range of from 50.degree. to 100.degree. C., preferably at about the boiling point of the organic solvent used. After completion of the hydrolysis, the reaction mixture is concentrated. If desired, the reaction mixture is treated with active charcoal prior to the concentration. The pH of the concentrated mixture is then adjusted to a pH of 2 with an acid, for example, hydrochloric acid or sulfuric acid, and is cooled to precipitate crude crystals. The crude crystals are then recrystalized from a suitable solvent, for example an aqueous solution of an alcohol to yield the purified final compound.
The starting compounds of general formula (II), 3-methyl-2-cyanomethylbenzo(b)furan and 5-substituted derivatives thereof, can be prepared, for example, by the process disclosed in DT-AS No. 1,203,277. They can also be prepared as follows:
Phenol or an appropriate p-substituted-phenol of formula ##STR5## wherein R is as hereinbefore defined, is reacted with an equimolar amount of sodium hydroxide in an aqueous medium to give a sodium salt of phenol or the p-substituted phenol respectively which is then treated with ethyl .alpha.-chloracetoacetate to yield a compound of formula ##STR6## wherein R is as hereinbefore defined. The ethyl .alpha.-(phenoxy)acetoacetate or ethyl-.alpha.-(p-substituted-phenoxy)acetoacetate obtained is then subjected to ring-closure by treatment with concentrated sulfuric acid to give 3-methyl-2-ethoxycarbonylbenzo(b)furan or a 5-substituted derivative thereof of formula ##STR7## wherein R is as hereinbefore defined. The resultant compound is subjected to reduction with lithium aluminium hydride in an organic solvent, e.g. diethyl ether, to give 3-methyl-2-hydroxymethylbenzo(b)furan or a 5-substituted derivative thereof of formula ##STR8## wherein R is as hereinbefore defined. This compound is then treated with thionyl chloride to give 3-methyl-2-chloromethylbenzo(b)furan or a 5-substituted derivative thereof of formula ##STR9## wherein R is as hereinbefore defined, which is then subjected to reaction with sodium cyanate to give 3-methyl-2-cyanomethylbenzo(b)furan or a 5-substituted derivative thereof of formula (II).
(B) Process using as a starting compound 3-methyl-2-acetylbenzo(b)furan or 5-substituted derivatives thereof having general formula (III). ##STR10## wherein R is as hereinbefore defined.
The starting compound, which can be obtained, for example, by the process described in Bull. Soc. Chim. Fr., 1970 (10), page 3601, is reacted with hydrogen sulfide or sulphur together with ammonia, a primary amine or a secondary amine in an aqueous solution or in an aqueous solution of organic solvent to obtain its thioamide.
Amines which may be used for this purpose include, for example, methylamine, pyridine, morpholin and the like.
The organic solvent which may be used for the reaction includes, for example, dioxane, piperidine and the like. It is also possible to use the amine as both the reaction material and the organic solvent. In the reaction, 0.01 mole to 2.0 mole, preferably 0.1 mole-1.5 moles of the starting compound is used per one liter of the total solvent. When morpholin is used as both the reaction material and the organic solvent, as for the amount of sulphur and morpholin, 1.3 to 1.7 moles, preferably 1.5 moles of both compounds are used per one mole of the starting material of general formula (III).
The reaction is preferably carried out at a temperature within the range of from 130.degree. to 200.degree. C. for about from 5 to 25 hours. After completion of the reaction, the reaction mixture is cooled to precipitate crystals of the thioamide. If desired, it is also possible to obtain the thioamide with a better yield by concentrating the reaction mixture, removing the solvent and adding water.
The thus-obtained thioamide is subjected to the hydrolysis with a suitable acid or alkali to give the desired 5-substituted-3-methyl-2-benzo(b)furylacetic acid represented by general formula (I). The acids which may with advantage be used for this purpose are exemplified by hydrochloric acid, sulfuric acid, paratoluenesulfonic acid and the like; and the alkalis which are preferably used for this purpose include for example hydroxides of alkali metals and alkaline earth metals such as sodium hydroxide, potassium hydroxide and calcium hydroxide. In the reaction, 0.01 mole to 1.0 mole, preferably 0.1 mole-0.5 mole of the starting compound is used per one liter of the total solvent.
The desired final product can be isolated for example in the following manner.
The reaction mixture containing the desired final product obtained by the hydrolysis is adjusted to a neutral pH for example with sodium carbonate and then washed with a suitable solvent such as for example benzene. After this, the water layer in the reaction solution is adjusted to an acidic pH 2, for example with a suitable dilute acid such as dilute hydrochloric acid, dilute sulfuric acid and the like to isolate the desired acid which is then extracted for example with ethylacetate and the like. After removal of water from the extract, the organic solvent of the extract is concentrated to obtain the desired crude product. The recrystallization is then carried out by the use of a suitable solvent such as, for example, an aqueous solution of alcohol, ethanol and the like.
Preferred physiologically acceptable salts of 3-methyl-2-benzo(b)furylacetic acid and the 5-substituted derivatives thereof of general formula (I) for incorporation into the pharmaceutical compositions according to the invention are, for example, the sodium, potassium, calcium and aluminium salts (obtained by reaction with the appropriate metal oxide or hydroxide) and also the physiologically acceptable non-toxic ammonium and amine salts (obtained by reaction with for example ammonia, diethylamine or triethanolamine).
The pharmaceutical compositions according to the present invention may with advantage be presented in a form suitable for internal or external administration, e.g. oral or topical administration, for example as tablets, granules, powders, capsules, ointments or creams which may be prepared in conventional manner.
Suitable daily dosages of the active compounds of general formula (I) whether administered internally or externally are generally in the range from 50 to 600 mg per man per day, depending upon the symptoms of the patient.
The compositions are preferably presented in the form of dosage units, each dosage unit being adapted to provide a fixed dose of active ingredient. Such compositions preferably contain from 25 to 100 mg of active ingredient per dosage unit.
Compositions in the form of tablets may be formulated with suitable amounts of various other ingredients such as, for example, excipients (e.g. lactose, glucose, sucrose or mannitol), disintegration agents (e.g. starch, sodium alginate, calcium carboxy-methylcellulose (CMC), crystal cellulose or sugar ester), lubricants (e.g. magnesium stearate or talc) and binding agents (e.g. simple syrup, gelatine solution, polyvinyl alcohol or polyvinylpyrrolidone). All of the abovementioned ingredients are used in the amounts conventionally used in the preparation of tablets. Dispersants (e.g. methylcellulose) and plasticizers may be used as coating agents for tablets.
Compositions according to the present invention presented in forms other than tablets and capsules, e.g. powders, preferably contain the active compounds of general formula (I) in amounts of from 5-10% by weight of the composition, together with other ingredients, generally excipients, e.g. lactose, glucose, sucrose and mannitol.
The acute toxicity, antiphlogistic and analgesic activities and the effect on gastric mucosa of 3-methyl-2-benzo(b)furylacetic acid and certain of the 5-substituted derivatives of general formula (I) according to the invention have been examined as described hereinafter. In the tests, the specimens Nos. 1-8 are the active compounds represented by the formula (I) according to the present invention and the specimens Nos. 9 and 10 are known compounds having known antipholgistic and analgesic activities included for comparison purposes.